Association of Successful Percutaneous Revascularization of Chronic Total Occlusions With Quality of Life

Key Points Question Is successful percutaneous revascularization of chronic total occlusions associated with improved quality of life? Findings This meta-analysis of 7 trials, including 2500 patients, found that successful chronic total occlusion revascularization was associated with improved quality of life parameters of patients compared with patients receiving optimal medical therapy or after failed chronic total occlusion revascularization. Meaning This study’s results may help physicians in their decision-making process when treating this high-risk group of patients.


Introduction
Chronic total occlusion (CTO) is reported in 15% to 25% of patients with stable coronary artery disease (CAD). 1 In daily clinical practice, the majority of patients with CTO are treated with optimal medical therapy (OMT), according to the current guidelines, which target (1) angina symptom reduction and (2) prevention of major adverse cardiovascular events (MACE). 2-4 Traditionally, CTO represents 1 of the most challenging lesion subsets in patients undergoing percutaneous coronary intervention (PCI), and CTO-PCI has been associated with low success rates and high complication rates. 5,6 Despite the advancements in strategies, materials, and the remarkable dedication of experienced operators, the legacy of earlier procedural failures still plagues the dissemination of percutaneous revascularization, with less than 10% of all CTOs being approached with PCI. 3,7 One of the main obstacles to broader adoption of CTO-PCI is the absence of robust evidence on the benefits of this treatment. Landmark studies in patients with CTO have suggested no difference in mortality between patients treated with PCI compared with OMT, although randomized trials searching for hard outcomes of CTO-PCI are strongly hampered by selection bias and low enrollment. [8][9][10] Recently, American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions 2021 Coronary Revascularization Guideline's class of recommendation on CTO treatment has been downgraded from IIA to IIB based on 2 randomized trials showing no improvement in left ventricle function following revascularization with a neutral effect on hard outcomes. 11 There is general agreement that the primary benefit of revascularization in chronic coronary syndromes is symptomatic improvement, convincingly confirmed using the Seattle Angina Questionnaire (SAQ) 12 in a substudy of the ISCHEMIA trial, 13 otherwise perceived as a negative trial in terms of hard clinical outcomes for revascularization. 14 In addition, quality of life scales are generally accepted as critical patient-reported outcome metrics for evaluating interventions in stable CAD. 15,16 Demonstrating comparable symptom relief and quality of life improvement with percutaneous CTO treatment can support the reappraisal of the class of recommendation and underscore the potential of CTO-PCI revascularization to improve patients' health status.
A recent review article studied patients' quality of life (QoL) following CTO revascularization and reported a trend of improvement in QoL indices. 17 Therefore, we conducted a systematic review and meta-analysis including all available trials assessing the life quality using validated SAQ metrics to test whether successful CTO-PCI is associated with improved quality of life.

Methods
This meta-analysis study was performed according to the Cochrane Collaboration, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist used for observational studies. [18][19][20] The study protocol was registered in the PROSPERO database before starting (CRD42022349139).

Included Studies and Patient Demographics
The flowchart for the search strategy and study inclusion is presented in Figure 1. The initial search strategy found 67 studies eligible for the full-text screening. Among those eligible for full-text screening, 37 were excluded due to a lack of SAQ metrics. We excluded 16 trials that defined revascularization as either PCI or CABG or with a follow-up shorter than 1 month. Seven substudies from included trials were also excluded. Finally, 7 studies 8,22-27 were eligible for inclusion in this metaanalysis, 3 were prospective randomized trials and 4 were prospective observational studies. We used the NOS to evaluate the 7 included studies as described previously. Detailed scores are presented in the eAppendix in Supplement 1. Moreover, the quality scores of these studies are shown in Table 1; the scores were 6 to 9 stars, indicating that the quality of these studies was reliable. They involved 2500 patients with a mean (SD) age of 61.2 (2.1) years; mean (SD) percentage male was 83.2% (89.8%) and mean (SD) percentage female was 16.8% (10.2%). Overall, 35.0% (7.9%) of patients had diabetes, 71.3% (8.5%) had hypertension, 71.6% (3.5%) had dyslipidemia, and 37.7%   Abbreviations: CTO-PCI, chronic total occlusion percutaneous coronary interventions; NOS, Newcastle-Ottawa Scale; OMT, optimal medical therapy.

Primary Outcome Analysis
Angina frequency was significantly improved following successful CTO-PCI in 5 out of the 7 contributing studies (2500 participants). The mean (SD) difference for SAQ-AF was 12.9 (3.1) survey points (95% CI, 7.1 to 19.8 survey points) and SMD was 0.54 (95% CI, 0.21 to 0.92; P = .002; I 2 = 86.4%) between successful CTO-PCI and combination of failed PCI and OMT. Additionally, metaregression analysis was performed using the baseline SAQ-AF, which was not found significant ( Figure 2A). Also, a longer interval between baseline and final assessment (point estimate, 0.03, 95% CI, 0.01 to 0.04; P = .01) was associated with a significant improvement in SAQ-AF. Age, gender, and medications such as calcium canal blockers, β-blockers, and nitrates, did not have an association with results.

Secondary Outcome Analysis
Results showed a similar favorable association of PL and QoL with the 2 secondary outcome parameters. PL was significantly reduced after successful CTO-PCI revascularization, with a mean (SD) difference of 9.7 (6.2) survey points (95% CI, 3.5 to 16.2 survey points) and SMD of 0.42 (95% CI, 0.24 to 0.55; P < .001, I 2 = 20.9%) ( Figure 2B). The QoL was reported in 4 out of 6 studies included and was significantly improved after successful CTO-PCI compared with failed PCI and OMT, with a mean (SD) difference of 14.9 (3.5) survey points (95% CI, 7.7 to 22.5 survey points) and SMD of 0.41 (95% CI, 0.25 to 0.61; P < .001, I 2 = 58.8%) ( Figure 2C).

Publication Bias
The bias evaluation confirmed a high-quality level for all studies included in the primary analysis (eAppendix in Supplement 1). Funnel plot analysis was performed in order to evaluate publication bias in RCTs and observational studies. Visual inspection of funnel plots did not show significant asymmetries, which was validated by the Egger test. The leave-one-out analysis was performed based on quality and to examine the importance of individual studies on the robustness of the primary and secondary outcomes (eAppendix in Supplement 1). There was no change in any outcome following the leave-one-out process.

Discussion
This meta-analysis included all currently available prospective randomized and observational studies to assess the association of successful CTO-PCI with patient life quality by using subscales of SAQ.
Notably, there was an improvement in SAQ scores in patients with CTO who were revascularized  Life quality changes are often considered soft outcomes compared with the so-called hard end points of death, recurrent myocardial infarction, and new revascularization procedures.
Controversially, patient-reported outcomes measures (PROMs) are critical components to assessing whether health care services and practices make a difference to a patient's life. PROMs are an assessment of health or well-being from the patient's perspective without interpretation by a clinician or health practitioner collected through patient-reported outcome measures. 28 The World Health Organization WHO states in its statute, "Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." 29 Therefore, knowledge of a consistent symptomatic improvement following CTO-PCI is essential for physicians when they discuss the potential benefits of this procedure before deciding treatment strategies. 30 A growing body of evidence indicates benefits, such as symptom improvement and reduced long-term health care costs following CTO-PCI. 31,32 Small trials managed to use objective measurable changes in exercise performance. The IMPACTOR-CTO trial (94 RCA-CTO patients randomized to CTO-PCI vs OMT alone) found a significant reduction in ischemic burden with an improvement in 6-minute walk distance. 9 In a study conducted by Sheehy et al, 33 78% of the patients were anginafree at 6 months following CTO-PCI. Our study adds to the literature by using the well-validated SAQ questionnaire. To our knowledge, this is the first meta-analysis to formally establish the association of successful CTO-PCI with functional and health status.
Most of the randomized CTO-PCI studies focused on hard end points, and this approach was encouraged by the results of some registries showing a survival benefit. [34][35][36][37] A different outcome cannot be excluded if a true all-comers trial with sufficiently long-term follow-up is conducted sticking to a strict policy not allowing crossover. In practice, such a trial is unlikely to be feasible and the ethics of a trial forcing half of patients randomized to OMT to live with disabling symptoms for years are questionable. We probably have to accept that, similar to other PCI in other chronic coronary syndromes, the only proven benefit of CTO-PCI is symptom relief. Treatments based on health status-related life quality are therefore becoming more critical in medical decision-making and are recommended by guidelines to aid in treatment strategies for CAD. 15 The higher procedural and in-hospital complications rate could have determined the worse long-term outcome of patients with failed procedures. This led us to perform a substudy dividing the  It is important to realize that there is a complex interaction between the CTO vessel and the other coronary arteries through the collateral channels that are present. Therefore, successful results were associated with improved myocardium globally. The EXPLORE trial randomized survivors of a STEMI within 7 days to get PCI or conservative management of a concomitant CTO to observe the alteration in left ventricle ejection fraction at 4 months. 10 In patients with concurrent CTO in the left anterior descending artery, left ventricle ejection fraction was significantly higher in the CTO-PCI group. Based on cardiovascular physiology, it is not perceived as a surprising finding to see such an improvement following revascularization. 40,41 It is a phenomenon called collateral (or coronary) steal that appears when the vasodilatory reserve is limited and defined as an absolute or relative fall in coronary blood flow to a vascular region in favor of another supply area under conditions of hyperemia, 42 which is undoubtedly the case of CTO vessel. The recent study analyzed the flow alternation in the collateral circulation in patients with CTO, before and after successful revascularization. 40 A significant reduction was shown in collateral flow over time following successful CTO-PCI.

Limitations
There are some limitations to this study. First, each study carries inherent selection bias invariably associated with patients' characteristics, CTO site, and time to last SAQ assessment. Second, beforeafter SMDs have some intrinsic limitations because the baseline and posttest scores are not independent. However, the between-group SMDs (as in our analysis) partially overcame this limitation because they reduced the association of these unmeasurable variables with results at least for the baseline evaluation. Another limitation was that we showed absolute improvement in patients' life quality using SAQ, instead of using certain thresholds for SAQ domains. The reason was the lack of patient-based data so we could not find patients with AF less than 60. Showing absolute improvement will be correlated much better with long-term outcomes, because some patients with successful CTO-PCI feel better due to physical improvement over time. Therefore, trapping between certain thresholds would limit our long-term estimate. Additionally, the sensitivity analyses and the meta-regression results might have been affected by the small number of the included studies and unmeasured confounding factors and must be interpreted with caution.